THe studies described herein are a continuation of our work over the past 6 years: 1) to characterize the defect(s) responsible for abnormal glucagon and insulin secretion in human diabetes and, 2) to define the respective metabolic consequences of glucagon excess and insulin lack. Specifically, we plan to investigate whether abnormal alpha and beta cell function in diabetes could result from a common glucoreceptor defect by testing the appropriateness of diabetic islet cell responses (stimulation and suppression): 1) to both hyper- and hypoglycemia; 2) to glucose anomers; 3) to nonglucose secretagogues and, 4) after sustained normoglycemia (prolonged infusion of insulin). We also plan to investigate the relative contributions of glucagon and insulin to diabetic hyperglycemia: 1) by assessing the effects on glucose tolerance of suppressing glucagon secretion with somatostatin and of infusing exogenous glucagon; 2) by quantifying changes in glucose production and utilization (measured by isotopic techniques using primed-continuous infusions of 3H3-glucose) during infusions of various combinations of glucagon and insulin; and 3) by characterizing the metabolic consequences of acute insulin withdrawal in totally pancreatectomized individuals lacking glucagon as well as insulin.